KRONIČNA LIMFOCITNA LEVKEMIJA

EHA, Stockholm 13.-16.6 2013 ASCO, Chicago , 2013

LYMPHOMA, Lugano 19.6.2013 KOLN, SEPT.2013

CLL:2013 update on diagnosis, risk stratification and treatment.Hallek M., AmJournal of

Haematology

Prim.Nataša Fikfak, dr.med., spec.int. In hematolog Splošna Bolnišnica Dr.Franca Derganca Nova Gorica

KLL-EHA 2013

• IMUNSKI SIGNAL PRI KLL ( B celični Receptor, signalna pot , inhibitorji )

• ALI SO POTREBNI NOVI PROGNOSTIČNI KAZALCI? ( mutacijski status pred in po terapiji, MRD personalizirano zdravljenje )

• STARA IN NOVA ZDRAVLJENJA ZA PONOVITEV KLL ( RFC,ofatumumab, lenalidomid,ibrutinib,idelalisib )

KRITERIJI ZA ZAČETEK ZDRAVLJENJA KLL

PROGRESIVNA, SIMPTOMATSKA ,AKTIVNA BOLEZEN

• Znaki odpovedovanja KM ( anemijain/ali trombocitopenija )

• Splenomegalija • Progresivna in / ali simptomatska limfadenopatija • Progresivna limfocitoza( >50% povečanje št.ly v 2

mes ) • Avtoimunska anemija in /ali trombocitopenija

neodzivna na GKS • B simptomi

Prvo zdravljenje KLL

Stadij Tel. zmogljivost

del(17p) p53mut

Zdravljenje

Binet A-B, Rai 0-II, neaktivna

bolezen Ni pomembno Ni pomembno /

Aktivna bolezen ali

Binet C ali Rai III-IV

„Go go“ Ne FCR

Da Allo-SCT

„Slow go“ Ne

KLB + anti-CD20-Mab (R ali GA-

101)

Da Al, HD R ali O

Hallek, Am J Hematol, prepub 2013

SPREMLJANJE ODGOVORA NA ZDRAVLJENJE

• Popolni odgovor,delni odgovor, stabilna bolezen,napredovanje bolezni, refraktarna bolezen

• MRD v kliničnih študijah ( 4 barvna pretočna citometrija , alelno specifična oligonukleotidna PCR )

Unmet medical need in CLL

• Despite major progress there remain important areas of improvement: – Less toxic therapies for unfit patients.

– Better therapies for high risk leukemia (del(17p),

p53 mutated, refractory).

Bcl-2 Mcl-1 Bcl-xL

B-cell Pathways

Cell Proliferation, Migration, Growth, Survival

Therapeutic modulation of B-cell receptor-dependent signaling in CLL

pre-BCR

Igα Igβ

P P Lyn

CD19

PI3K P Syk

Btk P

PLC-γ

PLC-γ P

PIP2 IP3

DAG Ca2+

IKK PKCβ

NF-κB ERK

ZDRAVLJENJE KLL

• NOVA, ŠE NE ODOBRENA ZDRAVILA ZA KLL skupina zdravilo tarča Pot aplikacije Razvojna st.

PROTITELO Obinutuzumab (GA101)

CD20 iv Faza III

blinatumomab CD3/CD19 iv fazaI

dacetuzumab CD40 iv fazaI

lucatumumab CD40 iv fazaII

mapatumumab TRAIL-R1 iv fazIb/II

mAb37.1 CD37 iv fazaI

NOVA ZDRAVILA ZA KLL skupina zdravilo tarča Pot aplikacije Faza razvoja

Genska terapija ISF35 (Adenovirus -CD154 )

CD40 Iv, intranodalno fazaI

SMIP TRU-016 CD37 iv fazaII

Skupina Zdravilo tarča Pot vnosa Faza razvoja

Bcl2 antagonisti

ABT-263 (Navitoclax)

Bcl-2 po fazaI/IIa

obatoclax Pan-Bcl2 iv fazaII

ABT-199 BH3mimetic po fazaII

TKI fostamatinib Syk po fazaI/II

Idelalisib ( Cal-101 )

PI3Kp110gama po fazaI

Ibrutinib ( PCI-32765 )

BTK po fazaI

skupina zdravilo tarča Pot vnosa Faza razvoja

Od ciklina odvisni KI

flavopiridol CDK iv fazaII

dinaciclib CDK1,2,5,9 iv fazaI

SNS-032 CDK 2,7,9 iv fazaI

mTOR inhibitor Everolimus (RAD001)

mTOR Iv/po fazaI/II

IMiD lenalidomid številne po fazaIII

Arzerra label in frontline CLL

‘Arzerra in combination with alkylator-based chemotherapy is indicated for the treatment of CLL in previously untreated patients considered inappropriate for fludarabine-based therapy’. (preliminarily supported by EU Rapporteur based on R label and similar submission, US still to be determined) Ba

se

‘Arzerra in combination with Chlorambucil is indicated for the treatment of CLL in previously untreated patients considered inappropriate for fludarabine-based therapy’. Do

wn

Issued: Wednesday 29 May 2013, London UK GSK and Genmab announce positive top-line results from pivotal trial of ARZERRA® (ofatumumab) combined with chlorambucil in previously untreated chronic lymphocytic leukaemia GlaxoSmithKline (GSK) plc and Genmab A/S (OMX: GEN) announced today that their Phase III study of ARZERRA® (ofatumumab) in combination with chlorambucil versus chlorambucil alone in patients with previously untreated chronic lymphocytic leukaemia (CLL) met its primary endpoint of progression free survival (PFS) as assessed by an independent review committee (IRC). A total of 447 patients were enrolled in the study. A 9.3 month improvement in the time a patient lived without worsening of their disease (median PFS) was seen in patients randomised to ofatumumab and chlorambucil compared to patients randomised to chlorambucil alone (22.4 months vs 13.1 months; HR: 0.57; p<0.001).

Emerging agents in CLL

• Antibodies – Anti-CD20 GA101 or obinutuzumab – Anti-CD37 antibodies or agents

• CDK Inhibitors • IMIDs - Lenalidomide • Inhibitors of BCR signaling pathways

– Bcl2 Antagonist: ABT-199 – PI3K Inhibitor GS-1101 – BTK Inhibitor PCI-32765 – Syk Inhibitor Fostamatinib – Dasatinib

GA101: Mechanisms of action

ADCC, antibody-dependent cell-mediated cytotoxicity CDC, complement-dependent cytotoxicity Mössner E, et al. Blood 2010; 115:4393−4402

17

Lower CDC Type II versus Type I antibody

Effector cell

Increased Direct Cell Death Type II versus Type I antibody

Enhanced ADCC Glycoengineering for

increased affinity to FcγRIIIa

CD20 FcγRIIIa

Complement GA101

B cell

• Veliko število starejših bolnikov s KLL in sočasnimi obolenji1,2

• V tej populaciji bolnikov: - Ni zadovoljivih dokazov da je trenutno zdravljenje boljše kot zdravljenje s KLB3

- Rezultati raziskav faze II so pokazali možnost kombinacije KLB + anti-CD20 protitelesi4,5

- Rezultati raziskav faze 1/2 so nadalje pokazali možnost zdravljenja s kemoimunoterapijo z novim tipom 2 anti-CD20 protitelesom - obinutuzumab (GA101)6,7

Cilji: pokazati, da je pri bolnikih s KLL in sočasnimi obolenji zdravljenje… … KLB + anti-CD20 mAb boljše kot monoterapija s KLB (stadij I raziskave) … GA101 + KLB boljše kot MabThera + KLB (stadij II)

CLL11: namen raziskave

1. Howlader N, et al. SEER Cancer Statistics Review, 1975-2010 5. Foa R, et al. Blood 2011; 118:294 2. Thurmes P, et al. Leuk Lymphoma 2008; 49:49-56 6. Morschhauser F, et al. Blood 2009; 114:884 3. Eichhorst B, et al. Blood 2009; 114:3382-3391 7. Goede V, et al. Leukemia 2012; 27:1172-1174 4. Hillmen P, et al. Blood 2010; 116:697. 18

CLL11: zasnova raziskave

• GA101: 1,000 mg dan 1, 8, in 15 1. cikla; dan 1 ciklov 2–6, na 28 dni • MabThera: 375 mg/m2 1. dan 1. cikla, 500 mg/m2 1. dan ciklov 2–6, na 28 dni • Klb: 0.5 mg/kg dan 1 in dan 15 ciklov 1–6, na 28 dni

• Bolniki z napredovalo boleznijo v klb roki so lahko prešli v roko Ga101-klb

RANDOMIZACIJA 1:2:2

MabThera + klorambucil x 6 ciklov

GA101 + klorambucil x 6 ciklov

Klorambucil x 6 ciklov Predhodno nezdravljeni KLL bolniki s sočasnimi obolenji CIRS* seštevek > 6 in/ali očistek kreatinina < 70 ml/min

Starost ≥ 18 let N = 780 (načrtovano)

Stadij I raziskave, N = 590

Dodatnih 190 bolnikov bo zaključilo stadij II

raziskave

Stadij II Ga101-klb proti Mab-klb

Stadij Ia Ga101-klb proti klb

Stadij Ib Mab-klb proti klb

*Cumulative Illness Rating Scale

19

CLL11: rezultati stadija I raziskave

http://meetinglibrary.asco.org/content/78884

SNOVI, KI VPLIVAJO NA BCR SIGNALNO POT

Bcl-2 Mcl-1 Bcl-xL

B-cell Pathways

Cell Proliferation, Migration, Growth, Survival

SNOVI, KI VPLIVAJO NA SIGNALNO POT BCR

• FOSTAMATINIB ( inhibitor Syk) • IDELALISIB ( CAL-101 ) = inhibitor PI3K • IBRUTINIB= inhibitor Brutonove TK • DASATINIB= inhibitor Src- in Abl- kinaze

• Rezultati :

Ibrutinib: Novel Small-Molecule Inhibitor of BTK

Forms a specific and irreversible bond with cysteine-481 in Btk

Potent Btk inhibition at IC50 = 0.5 nM

Orally bioavailable with daily dosing resulting in 24-hr target inhibition

Inhibits BCR signaling and active in spontaneous canine B-cell lymphoma

In CLL cells promotes apoptosis, inhibits ERK1/AKT phosphorylation, NF-κB DNA binding, CpG

mediated proliferation and stromal protection

N

N

N N

N H 2

O

N

O

PCI-32765

Honigberg LA, et al. Proc Natl Acad Sci USA.2010;107(29):13075-80. Herman SE, et al. Blood. 2011;117(23):6287-96.

Targeting BTK with Ibrutinib in relapsed CLL

J.Byrd et al., NEJM,June, 2013

• Faza Ib-2 • 85 bolnikov , relaps ali refraktarna KLL; 51/420mg/d • 34/840mg/d REZULTATI : • Stranski učinki st.1-2: diareja, utrujenost, okužbe

zgornjih dihal • OR ……71% • PR…….20/15% • PFS po 26 mes …..75%; OS…..83%

• Faza 2 : ibrutinib + BR • Ibrutinib + R Registracijske študije v ZDA : • -- relaps/refr KLL: ibrutinib / ofatumumab • -- relaps/refr:BR+/-ibrutinib • -- 1.zdravljenje : ibrutinib / klorambucil

IDELALISIB ( CAL – 101 )

• Stranski učinki : hiperglikemija, povečana aktivnost transaminaz ; mielosupresija, večje tveganje za okužbe

• Po 2x/d • Kombinacije : + ofatumumab, +

R,+bendamustin.+BR

IDELALISIB PRI NEZDRAVLJENIH KLL>65 let O’Brian et al,ASCO 2013

Št.bolnikov 64

Št.zdravljenih 50

Sr.starost 71 let

zdravljenje R375mg/m2/tx8+ idelalisib 150mg2x/d 48 tednov

ORR 97%

ORR pri TP53mut/del 100%

PFS pri 24 mes 93%

Overall Response Rates

Leonard J, et al. J Clin Oncol. 2013;31:[suppl; abstract 8617].

Rituximab Idelalisib

(N = 23/32)

Benda Idelalisib

(N = 28/33)

BR Idelalisib

(N = 10/14)

All combinations + Idelalisib (N = 61/79)

a Criterion for response [Cheson 2007].

0

60

80

100

Resp

onse

Rat

e ±9

5% C

I, %

0

20

40

60

80

100

19 % CR

27 % CR

43 % CR

20

40

26 % CR

85 %

72 % 71 % 78 %

Progression Free Survival – by cohort

0

25

50

75

100

Time from Start of Idelalisib (months)

0 6 12 18 24 30

Bendamustine + Idelalisib Rituximab + Idelalisib

BR + Idelalisib

Prog

ress

ion

free

(%)

Leonard J, et al. J Clin Oncol. 2013;31:[suppl; abstract 8617].

idelalisib

Študije : • --relaps/refr, not fit za KT : R+/- idelalisib • --relaps/refr : ofatumumab +/- idelalisib • Relaps / refr : BR+/-idelalisib

ZDRAVLJENJE KLL

• IMUNOMODULATORJI • --LENALIDOMID • --EVEROLIMUS

Študije lenalidomid pri KLL

• 1.linija pri starejših, še ne zdravljenih • Vzdrževalno zdravljenje KLL • Varnost in učinkovitost lenalidomida pri relapsu in

/ ali refraktarni KLL • Kombinacije : len+R len+R+F Bend+R+len flavopiridol+len len+ofatumumab

CLL

T cell

CD244; CD160, PD1:

CTLA4, TIM3,LAG3:*

CLL CD8+ T proliferation:

CLL CD8+ cytotoxicity :

Granzyme packaging:

Interferon-γ, TNFα:*

IL2:*

These changes are reversed by lenalidomide

Izčrpanje limfocitov T pri B celičnih limfoproliferativnih boleznih

Riches JC, et al. Blood. 2013;121:1612-21.

Repairing T-cells

CLL

T cell

ZDRAVLJENJE KLL

KOMBINIRANA KEMOTERAPIJA: - FC+/-mitoxantron - Cladribine/ cladribine + ciklofosfamid/ cladribine +ciklofosfamid + mitoxantron

ZDRAVLJENJE KLL

KEMOIMUNOTERAPIJA : • KOMBINACIJE Z RITUXIMABOM:

FCR;FCR lite; FCR+mitoxantron; pentostatin CR; BR;cladribine R,metilprednisolon RA:R+A

• KOMBINACIJE Z ALEMTUZUMABOM: FA,FCA, CFAR

• KOMBINACIJE NOVIH ZDRAVIL: FC+oblimersen

ZDRAVLJENJE KLL

ODLOČITEV O ZDRAVLJENJU(izkušnje,dobra klinična praksa,primerna uporaba diagnostičnih pripomočkov ) • Klinični stadij bolezni • Bolnikova fizična zmogljivost • Genetsko tveganje • Stopnja zdravljenja ( 1./2.izbor; odziv na

1.zdravljenje )

ZDRAVLJENJE KLL

• 1.LINIJA STADIJ FITNESS Del(17p)

p53mut ZDRAVLJENJE

Binet A-B Rai 0-II, neaktivna

nepomembno nepomembno Ni indicirano

Aktivna bolezen,Binet C,Rai III-IV

Go-Go ne FCR

da AloTKMC

Slow-go ne Clb+antiCD20

da Al,HD R,O

ZDRAVLJENJE KLL-2.linija ODZIV NA 1.ZDRAVLJENJE

FITNESS ZDRAVLJENJE

STANDARDNO ALTERNATIVNO(KL.ŠTUDIJA )

REFRAKTARNI/ PROGRES <2LET

GO-GO Al-Dex,FA, FCR AloTKMC

Len,BR,BR2,kombinacije z inhibitorji kinaz

SLOW-GO spremeni Z, kl.študija

Al za del(17p) FCRlite,BR, Bendamustin,len,ofatumumab,HD-R, inhibitorji kinaz

PROGRES>2LETI VSI Ponovi 1.linijo

There were no unexpected safety findings. The most common (≥1%) serious adverse events as reported by the investigator within 60 days of last treatment were neutropenia [including febrile neutropenia] (5%), anaemia (4%), pneumonia (4%), and pyrexia (2%). Infusion reactions were mild to moderate in severity with 3% of infusion reactions reported as serious. “As the aim of treating CLL, particularly in the frontline setting, is to maximise progression free survival while minimising side effects, we are therefore encouraged by these promising results.” said Dr. Kathy Rouan, Vice President BioPharmaceutical Development, GlaxoSmithKline. “We are planning regulatory submissions in the EU, US, and other regions in the coming months.” “We are delighted with the positive results from this trial which we believe may lead to ofatumumab plus chlorambucil as an additional treatment option for the care of patients with CLL,” said Jan van de Winkel, Ph.D., Chief Executive Officer of Genmab. “We look forward to submitting the study results, including secondary endpoints, to the International Workshop on CLL (iwCLL) in Cologne, Germany this September.” About the study This Phase III study (NCT00748189) included patients with previously untreated CLL considered inappropriate for fludarabine-based therapy. Patients in the study were randomised 1:1 to treatment with up to twelve cycles of ofatumumab in combination with chlorambucil or up to twelve cycles of chlorambucil alone. The primary endpoint of the study was PFS according to the International Workshop for Chronic Lymphocytic Leukaemia (iwCLL) updated 2008 National Cancer Institute-sponsored Working Group (NCIWG) guidelines, using an independent endpoints review committee.

About chronic lymphocytic leukaemia About ARZERRA (ofatumumab) Ofatumumab is not approved or licensed anywhere in the world for use in patients who have not received treatment for CLL. For Full US Prescribing Information, please visit: http://us.gsk.com/html/medicines/index.html and visit http://health.gsk.com/ for the EU SPC for the approved indication. Ofatumumab is a human monoclonal antibody which targets an epitope on the CD20 molecule encompassing parts of the small and large extracellular loops (Teeling et al 2006). Ofatumumab is being developed under a co-development and commercialization agreement between Genmab and GlaxoSmithKline. GlaxoSmithKline – one of the world’s leading research-based pharmaceutical and healthcare companies – is committed to improving the quality of human life by enabling people to do more, feel better and live longer. For further information please visit www.gsk.com Genmab A/S Genmab is a publicly traded, international biotechnology company specializing in the creation and development of differentiated human antibody therapeutics for the treatment of cancer. Founded in 1999, the company’s first marketed antibody, ofatumumab (Arzerra®), was approved to treat chronic lymphocytic leukaemia in patients who are refractory to fludarabine and alemtuzumab after less than eight years in development. Genmab’s validated and next generation antibody technologies are expected to provide a steady stream of future product candidates. Partnering of innovative product candidates and technologies is a key focus of Genmab’s strategy and the company has alliances with top tier pharmaceutical and biotechnology companies. For more information visit www.genmab.com

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